Thrombin is a multifunctional serine protease generated at sites of vascular injury. Its potent in vitro actions on platelets, leukocytes, vascular and mesenchymal cells suggest that thrombin may mediate not only hemostatic and thrombotic, but also inflammatory and proliferative responses in vivo. The thrombin receptor that was cloned and characterized by Dr. Coughlin appears to mediate many of these cellular events and provides a new tool for defining the relative importance of thrombin in various in vivo processes. We will address the hypotheses that thrombin receptor activation plays an important role in hemostasis, thrombosis, arterial restenosis, atherogenesis, and wound healing. The most expeditious and definitive approach is to introduce inactivating and activating mutations of thrombin receptor into mice by using embryonic stem cells and gene targeting by homologous recombination.